Contributors All authors contributed to either the conception and design, or analysis and interpretation of data, and to drafting the
article or revising it critically for important intellectual content. All authors also approved the final version to be published.

Revised 18 January 2012

Accepted 19 January 2012

Published Online First 24 May 2012

Abstract

Objective Heterocyclic amines (HAA) are animal carcinogens that are present in meat cooked at high temperature and in tobacco smoke.
These compounds require activation by cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase-2 (NAT2) before they can damage DNA. This study tested the hypotheses that well-done meat and cigarette
smoking increase the risk of adenoma, the precursor to most colorectal cancers, especially in individuals with rapid CYP1A2
and rapid NAT2 activities.

Design An endoscopy-based case–control study of adenoma was conducted among Caucasians, Japanese and native Hawaiians to test this
hypothesis. The overall diet and consumption of well-done meat cooked by various high-temperature methods were assessed by
interview in 1016 patients with a first adenoma and 1355 controls with a normal endoscopy. A caffeine test was used to assess
CYP1A2 and NAT2 activities in 635 cases and 845 controls. Logistic regression was used to account for matching factors and
potential confounders.

Results Smoking was associated with an increased risk of adenoma. Weak non-significant elevated OR were observed for the main effects
of HAA intakes or NAT2 activity. However, the combined effects of HAA intakes and NAT2 activity were statistically significant.
Subjects in both the upper tertiles of NAT2 activity and HAA intake were at increased risk of adenoma compared with subjects
in the lower tertiles of NAT2 activity and exposure (2-amino-3,4,8-dimethylimidazo[4,5-f]quinoxaline intake OR 1.70, 95% CI
I 1.06 to 2.75; 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline intake OR 1.91, 95% CI 1.16 to 3.16; and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
intake OR 2.14, 95% CI 1.31 to 3.49).

Conclusion The data suggest that rapid N-acetylators with high HAA intake may be at increased risk of adenoma.